Abnormal differentiation of myeloid cells is one of the immunological hallmarks of cancer. This manifests in suppressed differentiation of dendritic cells (DC), appearance of macrophages with immunosuppressive features and most prominently in accumulation of myeloid derived suppressor cells (MDSC). Data accumulated in recent years clearly indicate that myeloid cells are one of the major contributors to inability of immune system to develop and maintain antitumor immune responses. It is now clear that myeloid cell differentiation in cancer is affected by multiple tumor- derived factors. However, the mechanism of this effect remains elusive. We and others have recently determined that hyperactivation of Jak-STAT3 pathway is primarily responsible for the defects in DC differentiation and accumulation of MDSC. It is also critically important for macrophage function. Targeting this pathway may substantially improve myeloid cells differentiation and antitumor immune responses. Small molecules - inhibitors of Jak-STAT3 are currently being tested in advanced pre-clinical studies. However, it became increasingly clear that targeting such ubiquitous pathway, which is critically important for normal cell differentiation and survival will be very difficult. Therefore, it is important to identify more specific pathways that govern abnormal myeloid cell differentiation in cancer. This would not only provide better insight into the mechanisms of abnormal differentiation of myeloid cells in cancer but also may identify better targets for therapeutic intervention. We have generated preliminary data that strongly suggest that tumor-mediated defects in DC differentiation as well as accumulation of MDSC could be controlled by S100A9 protein. We have obtained S100A9 knockout and S100A9 transgenic mice that allowed not only to dissect possible role of this protein in myeloid cell differentiation but also can be used as a tool to identify the role of MDSC in tumor development and progression. Overall goal of this proposal is to identify novel mechanism regulating differentiation of DCs and MDSC in cancer and to identify the role of MDSC in tumor development associated with inflammation. To achieve this goal the following specific aims will be pursued: Specific Aim 1. Investigation the role of S100A9 in regulation of DC and myeloid cell differentiation; Specific Aim 2. Investigation the molecular mechanisms of S100A9 effects on DC and myeloid cell differentiation; Specific Aim 3. Investigation the role of myeloid-derived suppressor cells in tumor development. PUBLIC HEALTH RELEVANCE: Proposed research will investigate novel mechanism responsible for the abnormal differentiation of dendritic cells and myeloid cells in cancer, which play a critical role in immune defects in cancer. We will test novel hypothesis that decreased presence of dendritic cells and accumulation of myeloid-derived suppressor cells is caused by up-regulation of S100A9 protein. We will investigate the role of myeloid-derived suppressor cells in tumor development and progression. This mechanism may suggest a new approach to the treatment of immune defects associated with cancer.